1. Field of the Invention
The present invention relates to a process for improving the enantiometric purity of mixtures of optically active aldehyde isomers.
2. Description of Related Art
Asymmetric synthesis is of importance, for example, in the pharmaceutical industry, since frequently only one optically active isomer (enantiomer) is therapeutically active. An example of such a pharmaceutical product is the non-steroidal anti-imflammatory drug naproxen. The S enantiomer is a potent anti-arthritic agent while the R enantiomer is a liver toxin. It is therefore oftentimes desirable to selectively produce one particular enantiomer over its mirror image.
It is known that special precautions must be taken to ensure production of a desired enantiomer because of the tendency to produce optically inactive racemic mixtures, that is equal amounts of each mirror image enantiomer whose opposite optical activities cancel out each other. In order to obtain the desired enantiomer (or mirror image stereoisomer) from such a racemic mixture, the racemic mixture must be separated into its optically active components. This separation, known as optical resolution, may be carried out by actual physical sorting, direct crystallization of the racemic mixture, or other methods known in the art (see, for example, U.S. Pat. No. 4,242,193). Such optical resolution procedures are often laborious and expensive as well as destructive to the desired enantiomer. Due to these difficulties, increased attention has been placed upon asymmetric synthesis in which one of the enantiomers is obtained in significantly greater amounts than the other enantiomer. Efficient asymmetric synthesis desirably affords the ability to control both regioselectivity (branched/normal isomer ratio) and stereoselectivity.
Various asymmetric synthesis catalysts have been described in the art. For example, Wink, Donald J. et al., Inorg. Chem. 1990, 29, 5006-5008 discloses the synthesis of chelating bis(dioxaphospholane) ligands through chlorodioxaphospholane intermediates and the utility of bis(phosphite)rhodium cations in hydrogenation catalysis. A complex derived from dihydrobenzoin was tested as a precursor in the hydroformylation of olefins and gave a racemic mixture. Cationic rhodium complexes of bis(dioxaphospholane) ligands were tested in the hydrogenation of enamides and gave enantiomeric excesses on the order of 2-10%.
Pottier, Y. et al., Journal of Organometallic Chemistry, 370, 1989, 333-342 describes the asymmetric hydroformylation of styrene using rhodium catalysts modified with aminophosphinephosphinite ligands. Enantioselectivities greater than 30% ee are reportedly obtained.
East Germany Patents Nos. 275,623 and 280,473 relate to chiral rhodium carbohydrate-phosphinite catalyst production. The catalysts are stated to be useful as stereospecific catalysts for carrying out carbon-carbon bond formation, hydroformylation, hydrosilylation, carbonylation and hydrogenation reactions to give optically active compounds.
Stille et al., Organometallics 1991, 10, 1183-1189 relates to the synthesis of three complexes of platinum II-containing the chiral ligands: 1-(tert-butoxycarbonyl)-(2S, 4S)-2-[(diphenylphosphino)methyl]-4-(dibenzophospholyl)pyrrolidine; 1-(tertbutoxycarbonyl)-(2S,4S)-2-[(dibenzophos-pholyl)methyl]-4-(diphenylp hosphino)pyrrolidine; and 1-(tert-butoxycarbonyl)-(2S,4S)-4-(dibenzophospholyl)-2 -[(dibenzophospholyl)methyl]pyrrolidine. Asymmetric hydroformylation of vinyl arenes (including methoxyvinylnaphthalene) was examined with use of platinum complexes of these three ligands in the presence of stannous chloride as catalyst. Various branched/normal ratios (0.5-3.2) and enantiomeric excess values (12-77%) were obtained. When the reactions were carried out in the presence of triethyl orthoformate to improve on the enantiomeric purity of the products, all four catalysts gave virtually complete enantioselectivity (ee&gt;96%) and similar branched/normal ratios. A similar disclosure appears in published PCT patent application WO 88/08835
Published Patent Cooperation Treaty Patent Application 93/03839 (Babin et al.) relates to asymmetric syntheses processes in which a prochiral or chiral compound is reacted in the presence of an optically active metal-ligand complex catalyst to produce an optically active product. The processes of Babin et al. are distinctive in that they provide good yields of optically active products having high stereoselectivity, high regioselectivity, and good reaction rate without the need for optical resolution. The processes of Babin et al. stereoselectively produce a chiral center. An advantage of the processes of Babin et al. is that optically active products can be synthesized from optically inactive reactants. Another advantage of the processes of Babin et al. is that yield losses associated with the production of an undesired enantiomer can be substantially reduced. The asymmetric syntheses processes of Babin et al. are useful for the production of numerous optically active organic compounds, e.g., aldehydes, alcohols, ethers, esters, amines, amides, carboxylic acids and the like, which have a wide variety of applications. Despite the remarkable advance in the art represented by Babin et al, there remains further room for improvement with respect to the enantiomeric purity of the optically active aldehyde isomers produced by the Babin et al. processes.
Enantiomeric purification of enantiomerically enriched compounds (e.g., by crystallization) is a well known process and has been observed for many compounds. However, the ability to purify a chiral product via crystallization varies widely from compound to compound and even closely related compounds may behave very differently. There appears to be no prior art relating to the enantiomeric purification of enantiomerically enriched aldehyde mixtures, particularly mixtures of R- and S-2-(6-methoxy-2-naphthyl)propionaldehyde, by crystallization. The following publications are illustrative of prior art related to the crystallization of S-ibuprofen and S-naproxen acids, their sodium salts and 2-(6-methoxy-2-naphthyl)propionitrile from enantiomeric mixtures thereof. These references do not disclose crystallization of enantiomeric aldehyde mixtures.
Manimaran, T.; Stahly, G. P. Tetrahedron: Asymmetry 1993, 4, 1949, "Optical Purification of Profen Drugs," discloses the crystallization of the sodium salts of S-ibuprofen and S-naproxen. Crystallization of the sodium salts results in significant improvement in the enantiomeric purity of the product. The article includes phase diagrams for S-ibuprofen and S-naproxen acids and several salts of each. The article also describes some fundamental principles governing the enantiomeric purification of products via crystallization.
Manimaran, T.; Stahly, G. P.; Herndon, C. R., Jr. U.S. Pat. No. 5,248,813, 1993, "Enantiomeric Resolution," discloses the crystallization of various Ibuprofen salts as a means of improving enantiomeric purity.
Pringle, P.; Murray, W. T.; Thompson, D. K.; Choudhury, A. A.; Patil, D. R. U.S. Pat. No. 5,260,482, 1993, "Enantiomeric Resolution," discloses the use of hydrates of the sodium salt of ibuprofen in crystallization processes which result in enantiomeric purification of the product.
Rajanbabu, T. V.; Casalnuovo, A. L. J. Am. Chem. Soc. 1992, 114, 6265, "Tailored Ligands for Asymmetric Catalysis: The Hydrocyanation of Vinylarenes," discloses the preparation and use of catalysts for the hydrocyanation of vinylarenes as a route for the preparation of S-ibuprofen and S-naproxen. The authors comment, although no experimental details are given, that enantiomerically enriched mixtures of 2-(6-methoxy-2-naphthyl)propionitrile may be purified by crystallization.
The prior art relating to enantiomeric aldehyde mixtures does not disclose the use of crystallization to separate the enantiomers from each other. Thus, in the Stille et al. article discussed above, there is no mention of crystallizing aldehyde mixtures to improve their enantiomeric purity. Babin et al. discussed above discloses: "The desired optically active products, e.g., aldehydes, may be recovered in any conventional manner. Suitable separation techniques include, for example, solvent extraction, crystallization, distillation, vaporization, wiped film evaporation, falling film evaporation and the like. It may be desired to remove the optically active products from the reaction system as they are formed through the use of trapping agents as described in WO Patent 88/08835." Babin et al. does not disclose the use of crystallization to separate enantiomeric aldehydes from each other.